Myelin Distribution at the Optic Nerve Myelination Transition Zone Influences Axonal Biomechanics

Abstract

Purpose: The lamina cribrosa (LC) is considered the initial site of glaucomatous retinal ganglion cell (RGC) injury, and is also the region where unmyelinated RGC axons become myelinated. Here we sought to use finite element (FE) modeling to investigate how the configuration of the myelination transition zone (MTZ) influences the mechanical insult to RGC axons. Methods: A multiscale FE framework was developed to investigate the biomechanical effect of myelin distribution on IOP-induced axonal stress and strain at the MTZ. An anatomically based macro-scale FE eye model was used to compute LC deformations under 15 and 45 mmHg IOP. These deformations were then applied to micro-scale models of the posterior LC, consisting of axons, myelin sheaths, and surrounding matrix. Four distinct MTZ boundary configurations were simulated: one flat and three with random posterior offsets of 3, 6, or 9 {\mu}m, representing potential physiological variations. IOP-induced effective axonal strains and stresses were quantified across the different MTZ configurations. Results: Under IOP loading, axons exhibited longitudinal compression and transverse stretch, with marked effective stress and strain discontinuities at the myelin boundary. Across all models, the unmyelinated region exhibited higher effective stress and strain than the myelinated region, and this mechanical discontinuity increased with larger MTZ offsets. Conclusions: Glaucoma-associated demyelination has been previously suggested to precede RNFL thinning. Here we have shown that the MTZ configuration directly influences RGC axonal mechanics. Whether different MTZ profiles can initiate glaucomatous injury, whether demyelination accelerates disease progression, or whether both mechanisms contribute, remains to be determined.